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(Circulation. 1995;92:400-404.)
© 1995 American Heart Association, Inc.

Articles

Effects of Endothelin-1 and Endothelin-A Receptor Antagonist on Recovery After Hypothermic Cardioplegic Ischemia in Neonatal Lamb Hearts

Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90[pt 2]:I-422).

Takeshi Hiramatsu, MD; Joseph Forbess, MD; Takuya Miura, MD; Stephen J. Roth, MD; Mark A. Cioffi MAT; John E. Mayer, Jr, MD

From the Departments of Cardiac Surgery (T.H., J.F., T.M., M.A.C., J.E.M.) and Cardiology (S.J.R.), Children's Hospital and Harvard Medical School, Boston, Mass.

Background Prior studies suggest an important role for coronary endothelium in ischemia/reperfusion (I/R) injury. Decreased endothelial release of the vasodilator nitric oxide occurs after I/R, but the role of the endothelium-derived vasoconstrictor endothelin-1 (ET-1) in I/R is unknown.

Methods and Results We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal lamb hearts before and after 2 hours of 10°C cardioplegic ischemia and examined the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts. ET-1 levels in coronary sinus blood before ischemia and at 0 and 30 minutes of reperfusion in 8 control hearts were constant (2.2±1.2 fmol/L, 2.2±1.3 fmol/L, and 2.5±1.0 fmol/L, respectively). In group 2 (n=6), 10 µmol/L of BE-18257B was given just before reperfusion. In group 3 (n=8), 10 pmol/L ET-1 was given just before the start of reperfusion. At 30 minutes of reperfusion, the ET-A antagonist hearts had significantly greater recovery of LV systolic (positive dP/dt and dP/dt at V10) and diastolic function (negative dP/dt), coronary blood flow (CBF), and MO₂ compared with controls (P<.05). The ET-1 hearts showed significantly reduced recovery of LV systolic (positive maximum and volume-normalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P<.05).

Conclusions These results, combined with prior studies, suggest that I/R causes reduced production of endogenous vasodilators (eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continued presence of ET-1. This imbalance may contribute to I/R injury. ET-A receptor antagonists may be useful therapeutic agents in reducing the injury that results from I/R.

Key Words: endothelin • ischemia • reperfusion